Quinolonecarboxylic acids, particularly, those having a cyclopropyl group at the 1-position, a fluorine atom at the 6-position and an alkyl group (see JP-A-62-215572 and JP-A-63-264461), an alkoxy group (see JP-A-63-198664 and JP-A-62-252772) or a fluorine-substituted methoxy group (JP-A-5-255183) at the 8-position are known to have an excellent antibacterial activity.
For production of such a quinolonecarboxylic acid, there have heretofore been proposed various processes. However, it is not known yet to produce a quinolonecarboxylic acid having a cyclopropyl group at the 1-position, a fluorine atom at the 6-position and an alkyl group, an alkoxy group or a fluorine-substituted methoxy group at the 8-position, via an N-cyclopropyl-2-substituted-3,4-difluoroaniline or an anilinomethylenemalonic acid derived therefrom.
For production of an aniline wherein a cyclopropyl group is bonded to the nitrogen atom, there is a report on a process which comprises reacting 1-ethoxy-1-trimethylsiloxycyclopropane with aniline in the presence of sodium cyanoborohydride [Tetrahedron Letters, Vol. 36, 7399 (1995)]. In this process, however, an N,N-dicyclopropyl group-containing product is generated in a large amount as a by-product, resulting in a low yield of the intended N-cyclopropyl group-containing product.
There are also reports on a process which comprises reacting 1-ethoxy-1-trimethylsilyloxycyclopropane with phosphorus tribromide to produce 1-bromo-1-ethoxycyclopropane (which is a reactive derivative of 1-ethoxycyclopropane) and then reacting the compound with aniline to obtain an N-(1-ethoxycyclopropane) group-containing product, and a process which comprises reacting the N-(1-ethoxycyclopropane) group-containing product with sodium boron hydride and boron trifluoride-ether complex to obtain a next-stage corresponding product [J. Chem. Soc. Chem. Comm., 897, (1987)]. This process, however, includes a requisite step of producing 1-bromo-1-ethoxycyclopropane (which is thermally unstable) and therefore is inconvenient for industrial application.
Thus, industrial application of conventional processes for production of an aniline wherein a cyclopropyl group is bonded to the nitrogen atom and to production of an N-cyclopropyl-2-substituted-3,4-difluoroaniline (which is useful intermediate of the above-mentioned quinolonecarboxylic acids) has been disadvantageous and unsatisfactory in view of the yield obtained and the operability.
The present invention aims at providing processes for production, from an inexpensive raw material of high commercial availability, of N-cyclopropylanilines which are an important intermediate in producing a quinolonecarboxylic acid having a cyclopropyl group at the 1-position, a fluorine atom at the 6-position and an alkyl group, an alkoxy group or a fluorine-substituted methoxy group at the 8-position (this quinolonecarboxylic acid is a useful synthetic antibacterial agent); and intermediates therefor.
The present inventors made a study on an industrially advantageous process for producing a raw material used in production of a quinolonecarboxylic acid having a cyclopropyl group at the 1-position, a fluorine atom at the 6-position, and an alkyl group, an alkoxy group or a fluorine-substituted methoxy group at the 8-position (this quinolonecarboxylic acid has an excellent activity as a synthetic antibacterial agent), as well as on an intermediate therefor. As a result, it was found out that an N-alkoxycyclopropylaniline (which is an important intermediate for production of the above-mentioned quinolonecarboxylic acid) can be produced at a high yield by using a 3,4-difluoro-2-substituted-aniline of low cost and high industrial availability as a starting material and by reacting the starting material with a 1-alkoxy-1-trialkyl silyloxycyclopropane directly without using any conventional activation step such as bromination. It was also found out that the above-obtained N-alkoxycyclopropylaniline can be converted, by its reduction and subsequent reaction with a dialkyl alkoxymethylenemalonate, into an anilinomethylenemalonic acid; and that the anilinomethylenemalonic acid is a useful material for production of a quinolonecarboxylic acid having a cyclopropyl group at the 1-position, a fluorine atom at the 6-position and an alkyl group, an alkoxy group or a fluorine-substituted methoxy group at the 8-position; and that both the anilinomethylenemalonic acid-and its intermediates are novel compounds. These findings have led to the completion of the present invention.